Hypoxia or tobacco-smoke exposure induce region-specific microvascular remodeling in the brain

Chronic obstructive pulmonary disease (COPD) leads to a progressive decline in lung function, making it a leading cause of mortality worldwide. While COPD primarily affects the lungs, emerging research shows the life-threatening role of associated systemic changes affecting other organs, including the brain. However, the complex interplay between COPD and the brain’s microenvironment remains poorly understood. Here, we monitored alterations across several brain regions in mouse models subjected to chronic mild hypoxia (CMH) or tobacco-smoke exposure leading to pulmonary hypertension (S-PH) or also emphysema (S-Em). Brain microvasculature, microglia and hypoxia pathway states were analyzed by immunofluorescence and immunohistochemistry imaging of standard FFPE tissue sections. Quantitative evaluation revealed model-specific changes in microvascular density, with increased density in the CMH and S-Em and decreased density in the S-PH mice. 3D-imaging of cleared thick brain tissue sections by spinning-disc confocal microscopy corroborated these findings and, together with fibrinogen, MMP-9 and TIMP-1 immunoblot analyses, provided a comprehensive view of the distinct microenvironment states. Overall, our findings link lung dysfunction and associated changes in the brain microenvironment, which may be relevant to understanding the systemic comorbidities of chronic lung diseases, particularly altered brain conditions that may influence lung cancer metastasis.